C2 taxane derivaties and pharmaceutical compositions containing them

- Florida State University

Taxane derivatives having alternative C2 substituents.

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Claims

1. A taxane having the formula ##STR36## wherein X.sub.1 is --OX.sub.6, --SX.sub.7, or --NX.sub.8 X.sub.9;

X.sub.2 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.3 and X.sub.4 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.5 is --COX.sub.10, --COOX.sub.10, --COSX.sub.10, --CONX.sub.8 X.sub.10, or --SO.sub.2 X.sub.11;
X.sub.6 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group;
X.sub.7 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X.sub.8 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.9 is an amino protecting group;
X.sub.10 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.11 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OX.sub.10, or --NX.sub.8 X.sub.14;
X.sub.14 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R.sub.1 is hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate;
R.sub.2 is --OCOR.sub.31;
R.sub.4a is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, or --OCOR.sub.30;
R.sub.7a is hydrogen, halogen, or --OR.sub.28;
R.sub.9 is hydrogen or together with R.sub.9a forms an oxo;
R.sub.9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo;
R.sub.10 is hydrogen or together with R.sub.10a forms an oxo;
R.sub.10a is hydrogen, --OCOR.sub.29, hydroxy, or protected hydroxy, or together with R.sub.10 forms an oxo;
R.sub.14 is hydrogen, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate;
R.sub.28 is hydrogen, acyl, or hydroxy protecting group;
R.sub.29 and R.sub.30 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; and
R.sub.31 is substituted phenyl which is substituted with an alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, protected hydroxy, aryl, alkenyl, acyl, acyloxy, nitro, amino, or amido substituent.

2. The taxane of claim 1 wherein X.sub.31 is selected from the group consisting of ##STR37## and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.

3. The taxane of claim 2 wherein Z is methyl or methoxy.

4. The taxane of claim 1 wherein R.sub.9 is hydrogen or together with R.sub.9a forms an oxo; and R.sub.9a is hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo.

5. The taxane of claim 1 wherein

R.sub.14, R.sub.10, and X.sub.4 are hydrogen;
R.sub.10a is hydroxy or acetoxy;
R.sub.9 and R.sub.9a together form an oxo;
R.sub.7a, R.sub.1 and X.sub.1 are hydroxy;
R.sub.4a is acetoxy;
X.sub.3 is phenyl;
X.sub.5 is --COX.sub.10;
X.sub.10 is phenyl or t-butoxy; and
the taxane has the 2'R, 3'S configuration.

6. The taxane of claim 1 wherein

R.sub.14 and R.sub.10 are hydrogen;
R.sub.10a is hydroxy or acetoxy,
R.sub.9 and R.sub.9a together form an oxo,
R.sub.7a is hydroxy,
R.sub.4a is acetoxy,
X.sub.3 is substituted or unsubstituted alkyl or alkenyl;
X.sub.4 is hydrogen;
X.sub.5 is --COX.sub.10, --COOX.sub.10, or --CONX.sub.8 X.sub.10;
X.sub.10 is substituted or unsubstituted alkyl, alkenyl or aryl.

7. A pharmaceutical composition which contains the taxane of claim 1 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

8. A taxane having the formula ##STR38## wherein X.sub.5 is --COX.sub.10;

X.sub.10 is t-butoxy or phenyl;
R.sub.4a is acetoxy;
R.sub.10a is hydroxy or acetoxy;
R.sub.31 is substituted phenyl which is substituted with methoxy, methyl, chloro, fluoro, or trifluoromethyl; and
Ph is phenyl.

9. A taxane having the formula ##STR39## wherein X.sub.1 is --OX.sub.6, --SX.sub.7, or --NX.sub.8 X.sub.9;

X.sub.2 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.3 and X.sub.4 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.5 is --COX.sub.10, --COOX.sub.10, --COSX.sub.10, --CONX.sub.8 X.sub.10, or --SO.sub.2 X.sub.11;
X.sub.6 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group;
X.sub.7 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X.sub.8 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.9 is an amino protecting group;
X.sub.10 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X.sub.11 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OX.sub.10, or --NX.sub.8 X.sub.14;
X.sub.14 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R.sub.1 is hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate;
R.sub.2 is --OCOR.sub.31;
R.sub.41 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, or --OCOR.sub.30;
R.sub.7a is hydrogen, halogen, or --OR.sub.28;
R.sub.9 is hydrogen or together with R.sub.9a forms an oxo;
R.sub.9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo;
R.sub.10 is hydrogen or together with R.sub.10a forms an oxo;
R.sub.10a is hydrogen, --OCOR.sub.29, hydroxy, or protected hydroxy, or together with R.sub.10 forms an oxo;
R.sub.14 is hydrogen, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate;
R.sub.28 is hydrogen, acyl, or hydroxy protecting group;
R.sub.29 and R.sub.30 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; and
R.sub.31 is substituted phenyl which is substituted with an alkyl, alkoxy, chloro, bromo, iodo, trifluoromethyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, or amido substituent.

10. The taxane of claim 8 wherein

X.sub.10 is t-butoxy;
R.sub.10a is hydroxy; and
R.sub.31 is (m-methoxy)phenyl, (p-methoxy)phenyl, (m-methyl)phenyl, (m-chloro)phenyl, (p-chloro)-phenyl, (m-trifluoromethyl)phenyl, (m,m'-bis(trifluoromethyl))phenyl, (m,m'-dimethyl)phenyl, (o-trifluoromethyl)phenyl, or (o-methyl)-phenyl.

11. The taxane of claim 1 wherein

X.sub.1 is --OX.sub.6;
X.sub.4 is hydrogen;
X.sub.5 is --COX.sub.10, --COOX.sub.10, or --CONX.sub.8 X.sub.10;
X.sub.6 is hydrogen or hydroxy protecting group; and
X.sub.10 is substituted or unsubstituted alkyl, aryl, or heteroaryl.

12. The taxane of claim 1 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

13. The taxane of claim 11 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

14. The taxane of claim 9 wherein

X.sub.1 is --OX.sub.6;
X.sub.4 is hydrogen;
X.sub.5 is --COX.sub.10, --COOX.sub.10, or --CONX.sub.8 X.sub.10;
X.sub.6 is hydrogen or hydroxy protecting group; and
X.sub.10 is substituted or unsubstituted alkyl, aryl, or heteroaryl.

15. The taxane of claim 9 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

16. The taxane of claim 14 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

17. The taxane of claim 1 wherein R.sub.31 is selected from the group consisting of ##STR40## and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.

18. The taxane of claim 17 wherein

X.sub.1 is --OX.sub.6;
X.sub.4 is hydrogen;
X.sub.5 is --COX.sub.10, --COOX.sub.10, or --CONX.sub.8 X.sub.10;
X.sub.6 is hydrogen or hydroxy protecting group; and
X.sub.10 is substituted or unsubstituted alkyl, aryl, or heteroaryl.

19. The taxane of claim 17 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

20. The taxane of claim 18 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

21. The taxane of claim 17 wherein Z is methyl or methoxy.

22. The taxane of claim 1 wherein R.sub.31 is selected from the group consisting of ##STR41## and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.

23. The taxane of claim 22 wherein

X.sub.1 is --OX.sub.6;
X.sub.4 is hydrogen;
X.sub.5 is --COX.sub.10, --COOX.sub.10, or --CONX.sub.8 X.sub.10;
X.sub.6 is hydrogen or hydroxy protecting group; and
X.sub.10 is substituted or unsubstituted alkyl, aryl, or heteroaryl.

24. The taxane of claim 22 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

25. The taxane of claim 23 wherein

R.sub.1 is hydroxy;
R.sub.4a is --OCOR.sub.30;
R.sub.7a is hydroxy;
R.sub.14 is hydrogen; and
R.sub.30 is substituted or unsubstituted alkyl.

26. The taxane of claim 22 wherein Z is methyl or methoxy.

27. A pharmaceutical composition which contains the taxane of claim 9 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

28. The taxane of claim 1 wherein R.sub.14 is hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate; and R.sub.1 is as defined in claim 1.

29. The taxane of claim 1 wherein R.sub.1 together with R.sub.14 forms a carbonate.

30. The taxane of claim 9 wherein R.sub.14 is hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate; and R.sub.1 is as defined in claim 1.

31. The taxane of claim 9 wherein R.sub.1 together with R.sub.14 forms a carbonate.

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Patent History
Patent number: 5728725
Type: Grant
Filed: Jun 5, 1995
Date of Patent: Mar 17, 1998
Assignee: Florida State University (Tallahassee, FL)
Inventors: Robert A. Holton (Tallahassee, FL), Chunlin Tao (Tallahassee, FL)
Primary Examiner: Ba K. Trinh
Law Firm: Senniger, Powers, Leavitt & Roedel
Application Number: 8/462,124